ABSTRACT Defects in adipocyte function drive the onset of systemic insulin resistance and obesity-linked diabetes. Mitochondrial dysfunction is often associated with these obesity-induced abnormalities in adipocyte function. Agents that can revert these defects are clinically useful insulin sensitizers in humans. Using innovative tools, we recently isolated a small molecule that increased multiple aspects of adipocyte physiology and identified its target as Progesterone Receptor Membrane Component 2 (PGRMC2), a protein with no prior link to adipocyte function. The compound is not an inhibitor of PGRMC2, but rather, a gain-of-function ligand or activator. Treatment of obese-diabetic mice with a derivative of this molecule increased insulin sensitivity and glucose tolerance, indicating that activation of PGRMC2 function may be therapeutic. In contrast, adipose-specific PGRMC2-null mice exhibit profound defects in mitochondrial function, adaptive thermogenesis, and systemic glucose metabolism, highlighting the importance of PGRMC2 activity in adipocytes and systemic homeostasis. PGRMC2 is a poorly-characterized single-pass transmembrane protein with a putative heme-binding domain. It is localized in the endoplasmic reticulum and enriched in the nuclear envelope, and it reversibly binds heme. To stimulate adipocyte differentiation, chemical activation of PGRMC2 requires Rev-Erba, an adipogenic nuclear receptor whose natural ligand is heme, which suggests a role for PGRMC2 in heme trafficking. Heme is an essential prosthetic group for many proteins, and a signaling molecule in diverse biological processes. Because free heme is highly cytotoxic, heme-dependent processes require the rapid mobilization of heme to hemoproteins present in every organelle. Heme synthesis and degradation pathways are well known, but how heme synthesized in mitochondria reaches other organelles is not known. PGRMC2-null cells and tissues show alterations in intracellular heme partitioning, with decreased signaling heme in the nucleus. Thus, studying the function of PGRMC2 may provide the means to understand how heme is mobilized inside cells. Our hypothesis is that PGRMC2 plays a key role in intracellular heme homeostasis, facilitating heme delivery to the nucleus, and that this process is critical for adipocyte function and systemic physiology. This work may validate PGRMC2 as the first intracellular heme chaperone identified in mammals, one involved in transport of heme from mitochondria to the nucleus. It will also reveal the impact of heme metabolism on adipocyte function and systemic physiology. Further, because pharmacological activation of PGRMC2 has anti-diabetic effects, greater understanding of the function of PGRMC2 may provide the rationale to develop small-molecule PGRMC2 activators as insulin sensitizers.